WO1999044616A1 - Derives antibiotiques de steroides - Google Patents
Derives antibiotiques de steroides Download PDFInfo
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- WO1999044616A1 WO1999044616A1 PCT/US1998/004489 US9804489W WO9944616A1 WO 1999044616 A1 WO1999044616 A1 WO 1999044616A1 US 9804489 W US9804489 W US 9804489W WO 9944616 A1 WO9944616 A1 WO 9944616A1
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- unsubstituted
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- 0 CCCOC(C1)C(C)(C(CC2)[C@](C)C=I#I)C2C(CC2)C1C(C)(CC1)C2CC1OCC*=C Chemical compound CCCOC(C1)C(C)(C(CC2)[C@](C)C=I#I)C2C(CC2)C1C(C)(CC1)C2CC1OCC*=C 0.000 description 4
- GDOPTJXRTPNYNR-UHFFFAOYSA-N CC1CCCC1 Chemical compound CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 1
- TVEIKKVEOAALSM-QUFDWEOBSA-N CCC(CC1C2(C)CCCC1)C([C@](CCC1[C@H](C)CCC[O](C)=C)(C1(C)[C@H](C1)O)[I]=C)[C@@]21[IH]#C Chemical compound CCC(CC1C2(C)CCCC1)C([C@](CCC1[C@H](C)CCC[O](C)=C)(C1(C)[C@H](C1)O)[I]=C)[C@@]21[IH]#C TVEIKKVEOAALSM-QUFDWEOBSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0055—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Definitions
- the invention relates to novel steroid derivatives and salts thereof and the processes and intermediates for their preparation.
- Some compounds that associate strongly with the outer membrane of Gram-negative bacteria are known to disrupt the outer membrane and increase permeability.
- the increased permeability can lead directly to cell death or can increase the susceptibility of Gram-negative bacteria to other antibiotics.
- the best studied of this type of compound are the polymyxin antibiotics.
- polymyxin B For an example of a study involving the binding of polymyxin B to the primary constituent of the outer membrane of Gram- negative bacteria (lipid A) see: D. C. Morrison and D. M. Jacobs, Binding of Polymixin B to The Lipid a Portion of Bacterial Lipopolysaccharides, Immunochemistry 1976, vol. 13, 813-819.
- the present invention features compounds of the formula I
- R 5 , R 8 , R 9 , R 10 , R 13 , and R 14 is each independently: deleted when one of fused rings A, B, C, or D is unsaturated so as to complete the valency of the carbon atom at that site, or selected from the group consisting of hydrogen, hydroxyl, a substituted or unsubstituted (Cl-ClO) alkyl, (Cl-ClO) hydroxyalkyl, (Cl-ClO) alkyloxy- (Cl-ClO) alkyl, a substituted or unsubstituted (Cl-ClO) aminoalkyl, a substituted or unsubstituted aryl, Cl-ClO haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, oxo, a linking group attached to a second steroid, a substituted or unsubstituted (Cl-ClO) aminoal
- R_ through R 14 is an amino protecting group, and provided that at least two of R_ through R 14 are independently selected from the group consisting of a substituted or unsubstituted (Cl-ClO) aminoalkyloxy, a substituted or unsubstituted (Cl-ClO) aminoalkylcarboxy, a substituted or unsubstituted (Cl-ClO) aminoalkylaminocarbonyl, H2N-HC(Q5) -C (0) -0-, H2N-HC(Q5) -C(O) -N(H) -, (Cl-ClO) azidoalkyloxy, (Cl-ClO) cyanoalkyloxy, P.G.
- fused ring used herein can be heterocyclic or carbocyclic, preferably.
- saturated refers to the fused ring of formula I having each atom in the fused ring either hydrogenated or substituted such that the valency of each atom is filled.
- unsaturated refers to the fused ring of formula I where the valency of each atom of the fused ring may not be filled with hydrogen or other substituents .
- adjacent carbon atoms in the fused ring can be doubly bound to each other.
- Unsaturation can also include deleting at least one of the following pairs and completing the valency of the - 5 - ring carbon atoms at these deleted positions with a double bond; such as R 5 and R 9 ; R s and R 10 ; and R 13 and R 14 .
- unsubstituted refers to a moiety having each atom hydrogenated such that the valency of each atom is filled.
- halo refers to a halogen atom such as fluorine, chlorine, bromine, or iodine.
- An alkyl group is a branched or unbranched hydrocarbon that may be substituted or unsubstituted.
- branched alkyl groups include isopropyl, sec-butyl, isobutyl, tert-butyl, sec-pentyl, isopentyl, tert-pentyl, isohexyl .
- Substituted alkyl groups may have one, two, three or more substituents, which may be the same or different, each replacing a hydrogen atom.
- Substituents are halogen (e.g., F, Cl , Br, and I), hydroxyl, protected hydroxyl, amino, protected amino, carboxy, protected carboxy, cyano, methylsulfonylamino, alkoxy, acyloxy, nitro, and lower haloalkyl.
- halogen e.g., F, Cl , Br, and I
- substituted refers to moieties having one, two, three or more substituents, which may be the same or different, each replacing a hydrogen atom.
- substituents include but are not limited to halogen (e.g., F, Cl , Br, and I), hydroxyl, protected hydroxyl, amino, protected amino, carboxy, protected carboxy, cyano, methylsulfonylamino, - 6 - alkoxy, alkyl, acryl , acyloxy, nitro, and lower haloalkyl .
- An aryl group is a C 6 - 20 aromatic ring, wherein the ring is made of carbon atoms (e.g., C 6 _ 14 , C 6 _ 10 aryl groups) .
- haloalkyl include fluoromethyl , dichloromethyl, trifluoromethyl , 1 , 1-difluoroethyl , and 2 , 2 -dibromoethyl .
- a linking group is any divalent moiety used to link a compound of formula to another steroid, e.g., a second compound of formula I .
- An example of a linking group is (Cl-ClO) alkyloxy- (Cl-ClO) alkyl.
- a protecting group is not critical, provided that it is stable to the conditions of any subsequent reaction (s) on other positions of the compound and can be removed at the appropriate point without adversely affecting the remainder of the molecule.
- a protecting group may be substituted for another after substantive synthetic transformations are complete.
- a compound differs from a compound disclosed herein only in that one or more protecting groups of the disclosed compound has been substituted with a different protecting group, that compound is within the invention. Further examples and conditions are found in T.W. Greene,
- the present invention also includes methods of synthesizing compounds of formula I where at least two of - 7 -
- R_ through R 14 are independently selected from the group consisting of a substituted or unsubstituted (Cl-ClO) aminoalkyloxy.
- the method includes the step of contacting a compound of formula IV,
- R_ through R 14 are hydroxyl, and the remaining moieties on the fused rings A, B, C, and D are defined for formula I, with an electrophile to produce an alkyl ether compound of formula IV, wherein at least two of R x through R 14 are (Cl-ClO) alkyloxy .
- the alkyl ether compounds are converted into an amino precursor compound wherein at least two of R_ through R 14 are independently selected from the group consisting of (Cl-ClO) azidoalkyloxy and (Cl-ClO) cyanoalkyloxy and the amino precursor compound is reduced to form a compound of formula I .
- the electrophiles used in the method include but are not limited to 2- (2-bromoethyl) -1 , 3-dioxolane, - 8 -
- the invention also includes a method of producing a compound of formula I where at least two of R x through R 14 are (Cl-ClO) guanidoalkyloxy .
- the method includes contacting a compound of formula IV, where at least two of R_ through R 14 are hydroxyl, with an electrophile to produce an alkyl ether compound of formula IV, where at least two of R_ through R 14 are (Cl-ClO) alkyloxy .
- the allyl ether compound is converted into an amino precursor compound where at least two of R_ through R 14 are independently selected from the group consisting of (Cl-ClO) azidoalkyloxy and (Cl-ClO) cyanoalkyloxy.
- the amino precursor compound is reduced to produce an aminoalkyl ether compound wherein at least two of R_ through R 14 are (Cl-ClO) aminoalkyloxy.
- the aminoalkyl ether compound is contacted with a guanidino producing electrophile to form a compound of formula I .
- guanidino producing electrophile refers to an electrophile used to produce a guanidino compound of formula I .
- An example of an guanidino producing electrophile is HS0 3 -C ( ⁇ H) - ⁇ H 2 .
- the invention also includes a method of producing a compound of formula I where at least two of R_ through R 14 are H2N-HC (Q5) -C (O) -0- and Q5 is the side chain of any amino acid.
- the method includes the step of contacting a compound of formula IV, where at least two of R_ through R 14 are hydroxyl, with a protected amino acid to produce a protected amino acid compound of formula IV where at least two of at least two of R x through R 14 are P.G. -HN-HC(Q5) -C(0) -0- and Q5 is the side chain of any amino acid and P.G. is an amino protecting group.
- the protecting group of the protected amino acid compound is removed to form a compound of formula I .
- the present invention also includes pharmaceutical compositions of matter that are useful as antibacterial agents, sensitizers of bacteria to other antibiotics and disrupters of bacterial membranes.
- the pharmaceutical compositions can be used to treat humans and animals having a bacterial infection.
- the pharmaceutical compositions can include an effective amount of the steroid derivative alone or in combination with other antibacterial agents.
- the steroid derivatives act as bacteriostatic and bactericidal agents by binding to the outer cellular membrane of bacteria.
- the interaction between the steroid derivatives and the bacteria membrane disrupts the integrity of the cellular membrane and results in the death of the bacteria cell.
- compounds of the present invention also act to sensitize bacteria to other antibiotics. At concentrations of the steroid derivatives below the corresponding minimum bacteriostatic concentration, the derivatives cause bacteria to become more susceptible to other antibiotics by increasing the permeability of the outer membrane of - 10 - the bacteria.
- Measurements used to quantitate the effects of the steroid derivatives on bacteria include: measurement of minimum inhibitory concentrations (MICs) , measurement of minimum bactericidal concentrations (MBCs) and the ability of the steroid derivatives to lower the MICs of other antibiotics, e.g., erythromycin and novobiocin.
- MICs minimum inhibitory concentrations
- MMCs minimum bactericidal concentrations
- substitution refers to substituents on the fused steroid having the same stereochemical orientation.
- substituents R 3 , R 7 and R 12 are all ⁇ -substituted or ⁇ -substituted.
- the configuration of the moities R 3 , R 7 , and R 12 substituted on C3 , C7 , and C12 may be important for interaction with the cellular membrane.
- an effective amount of an anti-microbial composition comprising such a compound is administered to a host (including a human host) to treat a microbial infection.
- the compound by itself may provide the antimicrobial effect, in which case the amount of the compound administered is sufficient to be anti-microbial.
- an additional anti-microbial substance to be delivered to the microbial cells e.g., an antibiotic
- the compounds - 11 - can enhance the effectiveness of the additional antimicrobial substance. In some cases the enhancement may be substantial.
- Particularly important target microbes are bacteria (e.g., gram negative bacteria generally or bacteria which have a substantial (>40%) amount of a lipid A or lipid A-like substance in the outer membrane) .
- Other microbes including fungi, viruses, and yeast may also be the target organisms.
- the compounds can also be administered in other contexts to enhance cell permeability to introduce any of a large number of different kinds of substances into a cell, particularly the bacterial cells discussed above.
- the invention may be used to introduce other substances such as macromolecules (e.g., vector-less DNA) .
- the compounds according to the invention can be used to permeabilize a sperm cell.
- the invention can also be used to make antimicrobial compositions (e.g., disinfectants, antiseptics, antibiotics etc.) which comprise one of the above compounds.
- antimicrobial compositions e.g., disinfectants, antiseptics, antibiotics etc.
- These compositions are not limited to pharmaceuticals, and they may be used topically or in non-therapeutic contexts to control microbial (particularly bacterial) growth. For example, they may be used in applications that kill or control microbes on contact .
- the invention generally features methods of identifying compounds that are effective against a microbe by administering a candidate - 12 - compound and a compound according to the invention the microbe and determining whether the candidate compound has a static or toxic effect (e.g, an antiseptic, germicidal, disinfectant, or antibiotic effect) on the microbe.
- a static or toxic effect e.g, an antiseptic, germicidal, disinfectant, or antibiotic effect
- bacteria such as those discussed above are preferred.
- This aspect of the invention permits useful testing of an extremely broad range of candidate anti-microbials which are known to have anti-microbial effect in some contexts, but which have not yet been shown to have any effect against certain classes of microbes such as the bacteria discussed above.
- this aspect of the invention permits testing of a broad range of antibiotics currently thought to be ineffective against gram negative or lipid A-like containing bacteria.
- compositions which include one of the above compounds in combination with a substance to be introduced into a cell such as an antimicrobial substance as described in greater detail above.
- the compound and the additional substance may be mixed with a pharmaceutically acceptable carrier.
- the invention encompasses steroid derivatives that can be made by the synthetic routes described herein, and methods of treating a subject having a condition mediated - 13 - by a bacterial infection by administering an effective amount of a pharmaceutical composition containing a compound disclosed herein to the subject.
- the present invention provides the compounds of formula I described above.
- the preparation methods and the MIC and MBC of compounds of formula I are described.
- the cellular membrane permeability is also measured and described.
- Compounds that are useful in accordance with the invention, as described below, include novel steroid derivatives that exhibit bacteriostatic, bactericidal, and bacterial sensitizer properties.
- Those skilled in the art will appreciate that the invention extends to other compounds within the formulae given in the claims below, having the described characteristics. These characteristics can be determined for each test compound using the assays detailed below and elsewhere in the literature.
- Known compounds that are used in accordance with the invention and precursors to novel compounds according to the invention can be purchased, e.g., from Sigma Chemical Co., St. Louis; Aldrich, Milwaukee; Steroloids and Research Plus .
- Other compounds according to the invention can be synthesized according to known methods and the methods described below using publicly available precursors .
- the compounds of the present invention include but are not limited by amine or guanidine groups covalently - 14 - tethered to a steroid backbone, e.g., cholic acid.
- the backbone can be used to orient the amine or guanidine groups on one face of the steroid.
- Other steroid backbones also can be used, e.g., 5 member fused rings.
- the biological activity of the compounds can be determined by standard methods known to those of skill in the art, such as the "minimal inhibitory concentration (MIC)" assay described in the present examples, whereby the lowest concentration at which no change in optical density (OD) is observed for a given period of time is recorded as MIC.
- MIC minimum inhibitory concentration
- FIC fractional inhibitory concentration
- FICs can be performed by checkerboard titrations of compounds in one dimension of a microtiter plate, and of antibiotics in the other dimension, for example. The FIC is calculated by looking at the impact of one antibiotic on the MIC of the other and vice versa. An FIC of one indicates that the influence of the compounds is additive and an FIC of less than one indicates synergy. Preferably, an FIC of less than 0.5 is obtained for synergism. As used herein, FIC can be determined as follows: - 15 -
- This procedure permits determination of synergystic effects of the compound with other compounds.
- substances that generally may not be sufficiently effective against certain bacteria at safe dosages can be made more effective with the compound of the invention, thus enabling use of the substances against new categories of infections.
- many existing antibiotics are effective against some gram positive bacteria, but are not currently indicated to treat gram negative bacterial infection. In some cases, the antibiotic may be ineffective by itself against gram negative bacteria because it fails to enter the cell.
- Compounds of the invention may increase permeability so as to render the antibiotics effective against gram negative bacteria.
- fractional inhibitory concentration is also useful for determination of synergy between compounds of the invention in combination with other compounds having unknown anti -bacterial activity or in combination with other compounds, e.g., compounds which have been tested and show anti-bacterial activity.
- compounds of the invention may increase permeability so as to render compounds lacking antibacterial activity effective against bacteria.
- the FIC can also be used to test for other types of previously unappreciated activity of substances that will be - 16 - introduced into the cell by means of permeability enhancing compounds according to the invention.
- one mechanism of action is the lipid A interaction of multiple (usually three) moieties, which under phisiological conditions are positively charged, e.g., guanidino or amino moieties.
- the moieties extend away from the general plane of the remainder of the molecule, thus mimicing certain aspects of the structure of polymixins .
- compounds of the invention will generally be useful in the way that polymixins are useful.
- appropriate toxicity screens that permit selection of compounds that are not toxic at dosages that enhance microbial permeability.
- the invention also involves topical as well as non-therapeutic (antiseptic, germicidal, or disinfecting) applications in which the compounds are contacted with surfaces to be treated.
- contacting preferably refers to exposing the bacteria to the compound so that the compound can effectively inhibit, kill, or lyse bacteria, bind endotoxin (LPS) , or permeabilize gram- negative bacterial outer membranes.
- Contacting may be in vitro, for example by adding the compound to a bacterial culture to test for susceptibility of the bacteria to the compound.
- Contacting may be in vivo, for example administering the - 17 - compound to a subject with a bacterial disorder, such as septic shock.
- “Inhibiting” or “inhibiting effective amount” refers to the amount of compound which is required to cause a bacteriostatic or bactericidal effect.
- bacteria which may be inhibited include E. coli , P. aeruginosa, E. cloacae, S. typhimurium, M. Tuberculosis and S . aureus .
- the method of inhibiting the growth of bacteria may further include the addition of antibiotics for combination or synergistic therapy.
- antibiotics for combination or synergistic therapy.
- the appropriate antibiotic administered will typically depend on the susceptibility of the bacteria such as whether the bacteria is gram negative or gram positive, and will be easily discernable by one of skill in the art.
- antibiotics to be tested for synergistic therapy with the compounds of the invention include aminoglycosides (e.g., tobramycin) , penicillins (e.g., piperacillin) , cephalosporins (e.g., ceftazidime) , fluoroquinolones (e.g., ciprofloxacin) , carbepenems (e.g., imipenem) , tetracyclines and macrolides (e.g., erythromycin and clarithromycin) .
- the method of inhibiting the growth of bacteria may further include the addition of antibiotics for combination or synergistic therapy.
- antibiotics - 18 - include aminoglycosides (amikacin, gentamicin, kanamycin, netilmicin, tobramycin, streptomycin, azithromycin, clarithromycin, erythromycin, erythromycin estolate/ethylsuccinate/ gluceptate/lactobionate/stearate) , beta-lactams such as penicillins (e.g., penicillin G, penicillin V, methicillin, nafcillin, oxacillin, cloxacillin, dicloxacillin, ampicillin, amoxicillin, ticarcillin, carbenicillin, mezlocillin, azlocillin and piperacillin) , or cephalosporins (e.g., cephalosporins (e.g., cepicillin, kane, kanamycin, netilmicin, tobramycin, streptomycin, azithromycin, clarithromycin, erythromycin,
- antibiotics include carbapenems (e.g., imipenem) , monobactams (e.g., aztreonam) , quinolones (e.g., fleroxacin, nalidixic acid, norfloxacin, ciprofloxacin, ofloxacin, enoxacin, lomefloxacin and cinoxacin) , tetracyclines (e.g., doxycycline, minocycline, tetracycline) , and glycopeptides (e.g., vancomycin, teicoplanin) , for example.
- Other antibiotics include chloramphenicol, clindamycin, trimethoprim, sulfamethoxazole, nitrofurantoin, rifampin and mupirocin.
- the compounds may be administered to any host, including a human or non-human animal, in an amount effective to inhibit not only growth of a bacterium, but - 19 - also a virus or fungus. These compounds are useful as antimicrobial agents, antiviral agents, spermicidal agents, and antifungal agents.
- the compounds may be administered to any host, including a human or non-human animal, in an amount effective to inhibit not only growth of a bacterium, but also a virus or fungus. These compounds are useful as antimicrobial agents, antiviral agents, and antifungal agents.
- the compounds of the invention can be administered parenterally by injection or by gradual infusion over time.
- the compounds can be administered topically, intravenously, intraperitoneally, intramuscularly, subcutaneously, intracavity, or transdermally.
- Preferred methods for delivery of the compound include orally, by encapsulation in microspheres or proteinoids, by aerosol delivery to the lungs, or transdermally by iontophoresis or transdermal electroporation. Other methods of administration will be known to those skilled in the art.
- Preparations for parenteral administration of a compound of the invention include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
- non-aqueous solvents examples include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
- Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
- Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils.
- Intravenous -20 - vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like. Preservatives and other additives may also be present such as, for example, antimicrobials, anti-oxidants, chelating agents, and inert gases and the like.
- the invention provides a method of treating or ameliorating an endotoxemia or septic shock (sepsis) associated disorder, or one or more of the symptoms of sepsis comprising administering to a subject displaying symptoms of sepsis or at risk for developing sepsis, a therapeutically effective amount of a compound of the invention.
- ameliorate refers to a decrease or lessening of the symptoms of the disorder being treated.
- Such symptoms which may be ameliorated include those associated with a transient increase in the blood level of TNF, such as fever, hypotension, neutropenia, leukopenia, thrombocytopenia, disseminated intravascular coagulation, adult respiratory distress syndrome, shock and multiple organ failure.
- Patients who require such treatment include those at risk for or those suffering from toxemia, such as endotoxemia resulting from a gram-negative bacterial infection, venom poisoning, or hepatic failure, for example.
- patients having a gram-positive bacterial, viral or fungal infection may display symptoms of sepsis and may benefit from such a therapeutic method as described herein.
- Those patients who are more particularly able to benefit from the method of the invention are those suffering from -21 - infection by E. coli , Haemophilus influenza B, Neisseria eningi tidi s, staphylococci , or pneumococci .
- Patients at risk for sepsis include those suffering from gunshot wounds, renal or hepatic failure, trauma, burns, immunocompromised (HIV) , hematopoietic neoplasias, multiple myeloma, Castleman's disease or cardiac myxoma .
- the compounds may be incorporated into biodegradable polymers allowing for sustained release, the polymers being implanted in the vicinity of where delivery is desired, for example, at the site of an bacterial infection.
- the biodegradable polymers and their use are described in detail in Brem et al . , J. Neurosurg, 74:441-446 (1991).
- an effective amount of the compound is defined as the amount of the compound which, upon administration to a patient, inhibits growth of bacteria, kills bacteria cells, sensitizes bacteria to other antibiotics, or eliminates the bacterial infection entirely in the treated patient.
- the dosage of the composition will depend on the condition being treated, the particular derivative used, and other clinical factors such as weight and condition of the patient and the route of administration of the compound. However, for oral administration to humans, a dosage of 0.01 to 100 mg/kg/day, preferably 0.01-1 mg/kg/day, is generally sufficient.
- Effective doses will also vary, as -22 - recognized by those skilled in the art, dependent on route of administration, excipient usage, and the possibility of co-usage with other therapeutic treatments including other antibiotic agents.
- therapeutically effective amount refers to the amount of compound used is of sufficient quantity to decrease the subject's response to LPS and decrease the symptoms of sepsis.
- therapeutically effective therefore includes that the amount of compound sufficient to prevent, and preferably reduce by at least 50%, and more preferably sufficient to reduce by 90%, a clinically significant increase in the plasma level of TNF.
- the dosage ranges for the administration of compound are those large enough to produce the desired effect.
- the dosage will vary with the age, condition, sex, and extent of the infection with bacteria or other agent as described above, in the patient and can be determined by one skilled in the art.
- the dosage can be adjusted by the individual physician in the event of any contraindications.
- the effectiveness of treatment can be determined by monitoring the level of LPS and TNF in a patient. A decrease in serum LPS and TNF levels should correlate with recovery of the patient.
- patients at risk for or exhibiting the symptoms of sepsis can be treated by the method as described above, further comprising administering, substantially simultaneously with the therapeutic -23 - administration of compound, an inhibitor of TNF, an antibiotic, or both.
- intervention in the role of TNF in sepsis can prevent or ameliorate the symptoms of sepsis.
- an anti-TNF antibody as an active ingredient, such as a monoclonal antibody with TNF specificity as described by Tracey, et al. (Na ture, 330:662, 1987).
- a patient who exhibits the symptoms of sepsis may be treated with an antibiotic in addition to the treatment with compound.
- Typical antibiotics include an aminoglycoside, such as gentamicin or a beta-lactam such as penicillin, or cephalosporin or any of the antibiotics as previously listed above.
- a preferred therapeutic method of the invention includes administering a therapeutically effective amount of cationic compound substantially simultaneously with administration of a bactericidal amount of an antibiotic.
- administration of compound occurs within about 48 hours and preferably within about 2-8 hours, and most preferably, substantially concurrently with administration of the antibiotic.
- bactericidal amount refers to an amount sufficient to achieve a bacteria-killing blood concentration in the patient receiving the treatment.
- the bactericidal amount of antibiotic generally recognized as safe for administration to a human is well known in the art, and as is known in the -24 - art, varies with the specific antibiotic and the type of bacterial infection being treated.
- the compounds of the invention can be utilized as broad spectrum antimicrobial agents directed toward various specific applications. Such applications include use of the compounds as preservatives in processed foods when verified as effective against organisms including Salmonella, Yersinia, Shigella , either alone or in combination with antibacterial food additives such as lysozymes; as a topical agent (Pseudomonas, Streptococcus) and to kill odor producing microbes
- mycobacterium spp . have a waxy protective outer coating, and compounds of the invention in combination with antibiotics may provide enhanced effectiveness against Mycobaterial infection, including tuberculosis. In that case, the compounds could be -25 - administered nasally (aspiration) , by any of several known techniques.
- the permeability provided by the compounds may enchance introduction of a great variety of substances into microbes.
- the compounds may be used to enhance introduction of macromolecules such as DNA or RNA into microbes, particularly gram negative bacteria.
- macromolecules such as DNA or RNA
- phages e.g., phages
- the traditional vectors e.g., phages
- Conditions and techniques for introducing such macromolecules into microbes using the compounds of the invention will in most cases be routine.
- the formulations include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intraocular, intratracheal , and epidural) administration.
- the formulations may conveniently be presented in unit dosage form and may be prepared by conventional pharmaceutical techniques . Such techniques include the step of bringing into association the active ingredient and the pharmaceutical carrier (s) or excipient (s) .
- the formulations are prepared by uniformly and intimately bringing into associate the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
- Formulations of the present invention suitable for oral administration may be presented as discrete units - 26 - such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in- water liquid emulsion or a water-in-oil emulsion and as a bolus, etc.
- a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
- Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free- flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent.
- Molded tables may be made by molding, in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
- the tablets may optionally coated or scored and may be formulated so as to provide a slow or controlled release of the active ingredient therein.
- Formulations suitable for topical administration in the mouth include lozenges comprising the ingredients in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the ingredient to be administered in a suitable liquid carrier.
- Formulations suitable for topical administration to the skin may be presented as ointments, creams, gels and pastes comprising the ingredient to be administered in a pharmaceutical acceptable carrier.
- a preferred topical - 27 - delivery system is a transdermal patch containing the ingredient to be administered.
- Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.
- Formulations suitable for nasal administration wherein the carrier is a solid, include a coarse powder having a particle size, for example, in the range of 20 to 500 microns which is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
- Suitable formulations, wherein the carrier is a liquid, for administration, as for example, a nasal spray, aerosol, or as nasal drops include aqueous or oily solutions of the active ingredient.
- Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such as carriers as are known in the art to be appropriate.
- Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, other bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
- the formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and - 28 - may be stored in a freeze-dried (lyophilized) conditions requiring only the addition of the sterile liquid carrier, for example, water for injections, immediately prior to use.
- Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tables of the kind previously described.
- Preferred unit dosage formulations are those containing a daily dose or unit, daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the administered ingredient.
- formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example, those suitable for oral administration may include flavoring agents .
- the carrier in the pharmaceutical composition must be "acceptable” in the sense of being compatible with the active ingredient of the formulation (and preferably, capable of stabilizing it) and not deleterious to the subject to be treated.
- Examples 1-6 represent typical syntheses of compounds 1 through 48 as exemplified in Scheme 1 through 7.
- Example 7 represents MIC and MCB testing.
- Example 8 represents the ability of the compounds of formula I to lower the MICs of other antibiotics.
- Example 9 represents other compounds of formula I which can be synthesized using known starting materials and reaction schemes that are similar to those described herein. For example, the hydroxyl groups on cholic acid can be converted into amine by the method found in Hsieh et al . , Synthesis and DNA Binding Properties of C3-, C12-, and C24- Substituted Amino-Steroids Derived from Bile Acids, Biorganic and Medicinal Chemistry, 1995 , vol. 6, 823-838.
- Reagents (reaction correxa) a) 1AIH4, THF (98%) b) tritvichionde, Et 3 N, DMF (70%) c) allvlbromide, NaH, THF (96%). d) 0 3 , CH 2 Ck MeOH: Me-,S. NaBH 4 (95%) e) 9-BBN, THF. H 2 0 2 . NaOH (80%) f) MsCl.
- Reagents (reaction yields in parentheses), a) KCN. DMSO, MeOH, TsOH (92%) (b) MsCl, Et 3 N, CH -Cl* BnMeNH (88%) c) L1AIH 4 , AlCl* THF (50%).
- Reagents (reaction yields in parentheses), a) dicvcohexvlcarbodumide. N-hydroxvsuccinimide. methylphenvlamine, CH 2 C1 2 , MeOH (85%) b) L ⁇ AIH 4 , THF (82%) c) dicyclohexvicarbodiimide. dimethylaminopv ⁇ dine. Boc-giycme, CH 2 C (68%) d) dicyclohexvicarbodiimide. dimethvlaminopy ⁇ dine. Boc- ⁇ -aianme, CYi.C ⁇ , (72%) e) HCl. dioxane (-100%, -100%). -32 -
- Reagents (rea ⁇ ion yieids in parentheses): a) DIAD. Ph 3 P, / nitrobenzoic acid, THF (85%); NaOH, MeOH (85%). b) allvlbromide, NaH. THF (79%). c) 0 3 , CH 2 CI 2 , MeOH: Me ,S: NaBH (65%). d) MsCl. CH->CI 2 , Et 3 N (86%). e) NaN 3 , DMSO (80%). f) TsOH. MeOH (94%), g) MsCl. CHjC Et 3 N: N-benzyimethviamine (93%). g) LiAIH 4 , THF (94%).
- Reagents (reaction yields in parentheses): a) NaH, octyl bromide. DMF (80%); LiAlflTHF (60%). b) LiAIH,, THF (60%). • 33 -
- Reagents (reaction yields in parentheses): a) ethylene glycol, /.-toiuenesulfonic acid, benzene; NaOH, MeOH (96%). b) allylbromide, NaH, THF (90%). c) 9-BBN, THF: NaOH, H 362, H 2 0 (54%). d) pyridinium -toluenesulfonate, MeOH (98%). e) methanesulfonyl chloride, Et 3 N, CH,C1, ; NaN 3 , DMSO (88%). f) LiAlH 4 , THF (69%).
- methyl cholate (30.67 g, 72.7 mmol) in dry THF (600 mL) and LiAlH 4 (4.13 g, 109 mmol). After reflux for 48 hours, saturated aqueous Na 2 SO 4 (100 mL) was introduced slowly, and the resulted precipitate was filtered out and washed with hot THF and MeOH. Recrystallization from MeOH gave colorless crystals of 13 (28.0 g, 98% yield). m.p.
- HCl salt of compound 1 Compound 1 was dissolved in a minimum amount of CH 2 C1 2 and excess HCl in ether was added. Solvent and excess HCl were removed in vacuo and a noncrystalline -48 - white powder was obtained.
- Diisopropyl azodicarboxylate (DIAD) (1.20 mL, 6.08 mmol) was added to triphenylphosphine (1.60 g,
- Ozone was bubbled through a solution of 35 (0.551 g, 0.729 mmol) in CH 2 C1 2 (40 mL) and MeOH (20 mL) at -78°C until the solution turned a deep blue. Excess ozone was blown off with oxygen. Methylsulfide (1 mL) was added followed by the addition of NaBH 4 (0.22 g, 5.80 mmol) in 5% NaOH solution and methanol. The resulted mixture was stirred overnight at room temperature and washed with brine. The brine was then extracted with EtOAc (3 x 20 mL) . The combined extracts were dried over Na 2 S0 4 .
- Compound 41 was prepared following the method reported by D. H. R. Barton, J. Wozniak, S. Z. Zard, A Short And Efficient Degredation of The Bile Acid Side Chain . Some Novel Reactions of Sulphines And A- ketoesters, Tetrahedron, 1989, vol. 45, 3741-3754. A mixture of 41 (1.00 g, 2.10 mmol), ethylene glycol (3.52 mL, 63 mmol) and p-TsOH (20 mg, 0.105 mmol) was refluxed in benzene under N 2 for 16 hours. Water formed during the reaction was removed by a Dean-Stark moisture trap.
- Tryptic soy broth was made by dissolving 27.5 grams of tryptic soy broth without dextrose (DIFCO Laboratories) in 1 liter of deionized water and sterilizing at 121°C for 15 minutes.
- Solid agar (TSA) plates were made by dissolving 6.4 grams of tryptic soy broth and 12 grams of agar (purified grade, Fischer
- a suspension was prepared of E. coli (ATCC 10798) containing -10 6 CFU (colony forming units) /mL from a culture incubated in TSB at 37°C for 24 hours. Aliquots of 1 mL of the suspension were added to test tubes containing 1 mL TSB and incrementally varied concentrations of 1-12 and/or erythromycin or novobiocin. In the sensitization experiments, erythromycin or novobiocin were added 15 minutes later than 1-12. The - 85 - samples were subjected to stationary incubation at 37°C for 24 hours. Sample turbidity was determined by measuring absorption at 760 nm (HP 8453 UV-Visible Chemstation, Hewlett Packard) .
- the stereochemistry of the steroid backbone results in different activity of the cholic acid derivatives (compare 2 and 8, Tables 1, 2, 6 and 7) .
- Guanidine groups attached to the steroid provide lower MIC values than compounds containing amine groups (compare 1, 2, 4 and 5, compare Tables 1-8) .
- the length of the tether between the amine or guanidine groups and the steroid backbone also influences activity (compare 1-3, Tables 1, 2, 6 and 7) .
- Ester tethers between amine groups and the steroid backbone provide compounds with MIC values that - 86 - are higher than the corresponding compounds containing ether tethers (compare 1, 2, 6 and 7, Tables 1 and 2) .
- the group attached to the backbone at C-20 or C-24 also influences the activity of the cholic acid derivatives.
- a long carbon chain attached to the steroid via an ether linkage at C-24 lowers the MIC of the compound as compared to the compound with a hydroxyl group at C-24 (compare 2, 9 and 10, Tables 1, 2, 6 and 7) .
- Short chains of carbon or oxygen attached at C-20 decrease the MIC values of the cholic acid derivatives (compare 10 and 11, Tables 1 and 2) .
- Covalently linking the cholic acid derivatives increases the activity of the compounds (compare 10 and 12, Tables 1 and 2) .
- the R groups correspond to the side
- the R groups correspond to the side chain of any combination of amino chain of any combination of amino acids (D or L) acids (D or L)
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Abstract
Priority Applications (13)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU66911/98A AU759333B2 (en) | 1998-03-06 | 1998-03-06 | Steroid derived antibiotics |
CA002322847A CA2322847C (fr) | 1998-03-06 | 1998-03-06 | Derives antibiotiques de steroides |
CNB988138611A CN100398109C (zh) | 1998-03-06 | 1998-03-06 | 甾族化合物衍生的抗生素 |
DE69824638T DE69824638T2 (de) | 1998-03-06 | 1998-03-06 | Antibiotische steroidderivate |
PCT/US1998/004489 WO1999044616A1 (fr) | 1998-03-06 | 1998-03-06 | Derives antibiotiques de steroides |
JP2000534218A JP2002505292A (ja) | 1998-03-06 | 1998-03-06 | ステロイド由来抗生物質 |
BRPI9815711-6A BR9815711B1 (pt) | 1998-03-06 | 1998-03-06 | Composto antibiótico derivado de esteróide |
AT98909028T ATE269086T1 (de) | 1998-03-06 | 1998-03-06 | Antibiotische steroidderivate |
EP98909028A EP1058552B1 (fr) | 1998-03-06 | 1998-03-06 | Derives antibiotiques de steroides |
US09/234,008 US6350738B1 (en) | 1998-03-06 | 1999-01-19 | Steroid derived antibiotics |
US09/927,926 US6486148B2 (en) | 1998-03-06 | 2001-08-10 | Steroid derived antibiotics |
US09/930,316 US6767904B2 (en) | 1998-03-06 | 2001-08-15 | Steroid derived antibiotics |
US10/892,828 US7598234B2 (en) | 1998-03-06 | 2004-07-16 | Steroid derived antibiotics |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/US1998/004489 WO1999044616A1 (fr) | 1998-03-06 | 1998-03-06 | Derives antibiotiques de steroides |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
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US09/234,008 Continuation-In-Part US6350738B1 (en) | 1998-03-06 | 1999-01-19 | Steroid derived antibiotics |
US09/930,316 Continuation-In-Part US6767904B2 (en) | 1998-03-06 | 2001-08-15 | Steroid derived antibiotics |
Publications (1)
Publication Number | Publication Date |
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WO1999044616A1 true WO1999044616A1 (fr) | 1999-09-10 |
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Application Number | Title | Priority Date | Filing Date |
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PCT/US1998/004489 WO1999044616A1 (fr) | 1998-03-06 | 1998-03-06 | Derives antibiotiques de steroides |
Country Status (9)
Country | Link |
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EP (1) | EP1058552B1 (fr) |
JP (1) | JP2002505292A (fr) |
CN (1) | CN100398109C (fr) |
AT (1) | ATE269086T1 (fr) |
AU (1) | AU759333B2 (fr) |
BR (1) | BR9815711B1 (fr) |
CA (1) | CA2322847C (fr) |
DE (1) | DE69824638T2 (fr) |
WO (1) | WO1999044616A1 (fr) |
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JP2003512474A (ja) * | 1999-10-25 | 2003-04-02 | ホリス − イーデン ファーマスーティカルズ、 インコーポレイテッド | 血液細胞欠乏症の治療処置 |
US6635629B2 (en) | 2000-04-28 | 2003-10-21 | Inflazyme Pharmaceuticals Ltd. | 3-nitrogen-6,7-dioxygen steroids and uses related thereto |
WO2005018618A1 (fr) * | 2003-08-23 | 2005-03-03 | Korea United Pharm, Inc | Preparation d'un comprime stable a l'absorption de l'humidite et a dissolution rapide contenant du cefuroxime axetil et procede de fabrication correspondant |
US7141559B2 (en) | 2002-06-19 | 2006-11-28 | Karo Bio Ab | Glucocorticoid receptor ligands for the treatment of metabolic disorders |
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Families Citing this family (2)
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US6350738B1 (en) * | 1998-03-06 | 2002-02-26 | Brigham Young University | Steroid derived antibiotics |
JP2017031201A (ja) * | 2016-09-30 | 2017-02-09 | ブリガム ヤング ユニバーシティ | 口腔ケア組成物 |
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Also Published As
Publication number | Publication date |
---|---|
AU6691198A (en) | 1999-09-20 |
EP1058552A4 (fr) | 2001-09-19 |
EP1058552B1 (fr) | 2004-06-16 |
DE69824638D1 (de) | 2004-07-22 |
CA2322847C (fr) | 2008-05-13 |
AU759333B2 (en) | 2003-04-10 |
JP2002505292A (ja) | 2002-02-19 |
ATE269086T1 (de) | 2004-07-15 |
BR9815711B1 (pt) | 2014-10-29 |
CN1294514A (zh) | 2001-05-09 |
CN100398109C (zh) | 2008-07-02 |
EP1058552A1 (fr) | 2000-12-13 |
DE69824638T2 (de) | 2005-06-23 |
BR9815711A (pt) | 2001-11-13 |
CA2322847A1 (fr) | 1999-09-10 |
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